Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Evolution preserves social attention due to its key role in supporting survival. Humans are attracted to social cues from infancy, but the neurobiological mechanisms for the development of social attention are unknown. An evolutionary-based, vertical-hierarchical theoretical model of self-regulation suggests that neonatal brainstem inputs are key for the development of well-regulated social attention. Neonates born preterm (N = 44, GA 34 w.) were recruited and diagnosed at birth as a function of their auditory brainstem evoked responses (ABR). Participants enrolled in a prospective 8-year-long, double-blind, follow-up study comparing participants with brainstem dysfunctions and well-matched controls. Groups had comparable fetal, neonatal, and familial characteristics. Methods incorporated EEG power analysis and gaze tracking during the Attention Network Test (ANT, four cue types, and two targets) and a Triadic Gaze Engagement task (TGE, three social cue levels). Results showed that neonatal brainstem compromise is related to long-term changes in Alpha- and Theta-band power asymmetries (p < .034, p < .016, respectively), suggesting suppressed bottom-up input needed to alert social attention. Gaze tracking indicated dysregulated arousal-modulated attention (p < .004) and difficulty in gaze engagement to socially neutral compared to nonsocial cues (p < .012). Integrating models of Autism and cross-species data with current long-term follow-up of infants with discrete neonatal brainstem dysfunction suggests neonatal brainstem input as a gateway for bottom-up regulation of social attention.